ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, Sept. 2004, p.

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0066-4804/04/$08.000 DOI: 10.1128/AAC.48.9.36423643.2004

Vol. 48, No. 9

Moxifloxacin Treatment of Tuberculosis

We are pleased to see that the study of Pletz et al. (6)
confirms our earlier observations that moxifloxacin is active in
patients with pulmonary tuberculosis with positive sputum
smears (3). However, some of their results differ from ours,
and we believe that this is due to the method that they adopted.
In our study, we recruited groups of 15 subjects (3) and found
that moxifloxacin was significantly less active than isoniazid
when the time to reduce the viable bacillus count by 50%
(vt50) was calculated (1), but like Pletz et al., we found no
significant difference between the two drugs when early bactericidal activity (EBA) was calculated (3, 5, 6). The most important reason for this difference is the number of patients in
the groups recruited by Pletz et al. is small, and thus, the
absence of a statistically significant difference cannot be construed as indicating biological equivalence. Second, the EBA
methodology that Pletz et al. use is a variation of the standard
method (4), which calculates the value for EBA over 5 days
rather than 2 days and has limited power to distinguish between different drugs (5). The EBA methodology produces
large confidence intervals, and for this reason, studies have
shown that the results for isoniazid are poorly reproducible
between centers (7). Third, by grouping the data from different
patients together, the errors are enlarged. Viable counts of
mycobacteria from sputum vary enormously between patients
(often by more than 1 order of magnitude) and from day to
day. As the EBA measure is half (or a fifth) of the ratio
between the day 0 and day 2 (or day 5) values expressed
logarithmically, small variations in sputum mycobacterial viable counts result in large variations in the EBA values as found
in the study of Pletz et al.
We agree with the authors strategy of measuring the sputum
mycobacterial viable count over 5 days, but by recording only
three values and not calculating a regression line, they lose
much of the benefit of the longer period of observation. As
discussed in our previous papers (13), by taking measurements daily over the 5-day trial period, it is possible to use
nonlinear regression, which permits discrepant values to be
identified and removed. Moreover, vt50 has been shown to be
a measure which is comparable in different countries (2).
For these reasons, we believe that, although this paper is
useful in that it confirms that moxifloxacin is bactericidal in
patients with pulmonary tuberculosis with positive smears, its
conclusion that this compound is as active as isoniazid is misleading. Further studies are required to understand the optimal use of new highly active quinolones, such as moxifloxacin,
in pulmonary tuberculosis and whether they add to the activity
of isoniazid.

bactericidal activity of isoniazid in pulmonary tuberculosis. Optimization of

methodology. Am. J. Respir. Crit. Care Med. 156:918923.
5. Jindani, A., V. Aber, E. Edwards, and D. Mitchison. 1980. The early bactericidal activity of drugs in patients with pulmonary tuberculosis. Am. Rev.
Respir. Dis. 121:939949.
6. Pletz, M. W., A. De Roux, A. Roth, K. H. Neumann, H. Mauch, and H. Lode.
2004. Early bactericidal activity of moxifloxacin in treatment of pulmonary
tuberculosis: a prospective, randomized study. Antimicrob. Agents Chemother. 48:780782.
7. Sirgel, F. A., P. R. Donald, J. Odhiambo, W. Githui, K. C. Umapathy, C. N.
Paramasivan, C. M. Tam, K. M. Kam, C. W. Lam, K. M. Sole, and D. A.
Mitchison. 2000. A multicentre study of the early bactericidal activity of
anti-tuberculosis drugs. J. Antimicrob. Chemother. 45:859870.

*Phone: 44 2077940500
Fax: 44 2077940433
E-mail: rolygos@aol.com

Authors Reply
Both the study of Gosling et al. (1) and our study (4) used
isoniazid as a comparator to moxifloxacin, but different analyses were performed in the two studies. Our study was based
on the classical parameter of EBA over 5 days. When the
EBAs of moxifloxacin and isoniazid were compared, there was
no statistically significant difference. Our conclusion was that
the activity of moxifloxacin is comparablewe did not write
equalto that of isoniazid. This was not based on the absence
of a statistically significant difference but rather on the following data. (i) The reduction in the number of CFU per milliliter
over 5 days was more pronounced in the moxifloxacin group
than in the isoniazid group (from 14 17.2 to 0.7 0.9
CFU/ml for moxifloxacin versus 11.5 8.7 to 1.2 0.15
CFU/ml for isoniazid). (ii) The EBA of moxifloxacin was
greater than the EBA of isoniazid (0.273 for moxifloxacin and
0.209 for isoniazid). (iii) Calculating 95% confidence intervals
revealed that moxifloxacin had at least 61.6% of the antimycobacterial activity of isoniazid despite the deviation of the
data.
Our conclusion is also supported by results of animal studies
which showed that the bactericidal activity of moxifloxacin is
comparable to that of isoniazid (2, 3). Furthermore, Nuermberger et al. showed in a mouse model that the replacement of
isoniazid by moxifloxacin in the standard regimen increased
the activity dramatically, resulting in earlier culture negativity
(E. Nuermberger, T. Yoshimatsu, S. Tyagi, W. Bishai, and J.
Grosset, Abstr. 43rd Intersci. Conf. Antimicrob. Agents Chemother., abstr. 1035, 2003).
In conclusion, we agree with Gosling et al. that the discrepancy in our studies regarding the comparison of moxifloxacin
to isoniazid is caused by the different parameters (EBA versus
vt50) used, but on the basis of our results and the results of
several animal studies, we maintain that moxifloxacin and isoniazid have comparable activities. However, larger studies using clinical endpoints, such as time to culture negativity, are
required to identify the drug with the best clinical activity.

REFERENCES
1. Gillespie, S. H., R. D. Gosling, and B. M. Charalambous. 2002. A reiterative
method for calculating the early bactericidal activity of antituberculosis drugs.
Am. J. Respir. Crit. Care Med. 166:3135.
2. Gosling, R. D., L. Heifets, and S. H. Gillespie. 2003. A multicentre comparison of a novel surrogate marker for determining the specific potency of
anti-tuberculosis drugs. J. Antimicrob. Chemother. 52:473476.
3. Gosling, R. D., L. O. Uiso, N. E. Sam, E. Bongard, E. G. Kanduma, M.
Nyindo, R. W. Morris, and S. H. Gillespie. 2003. The bactericidal activity
of moxifloxacin in patients with pulmonary tuberculosis. Am. J. Respir.
Crit. Care Med. 168:13421345. (First published 13 August 2003; 10.1164/
rccm.200305682OC.)
4. Hafner, R., J. Cohn, D. Wright, N. Dunlap, M. Egorin, M. Enama, K. Muth,
C. Peloquin, N. Mor, L. Heifits, and the DATRI 008 Study Group. 1997. Early

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Roland Gosling*
Stephen Gillespie
Department of Medical Microbiology
Royal Free and University College
Pond Street
London NW3 2PF
United Kingdom

VOL. 48, 2004

LETTERS TO THE EDITOR

REFERENCES

1. Gosling, R. D., L. O. Uiso, N. E. Sam, E. Bongard, E. G. Kanduma, M.

Nyindo, R. W. Morris, and S. H. Gillespie. 2003. The bactericidal activity of
moxifloxacin in patients with pulmonary tuberculosis. Am. J. Respir. Crit.
Care Med. 168:13421345. (First published 13 August 2003; 10.1164/
rccm.200305682OC.)
2. Ji, B., N. Lounis, C. Maslo, C. Truffot-Pernot, P. Bonnafous, and J. Grosset.
1998. In vitro and in vivo activities of moxifloxacin and clinafloxacin against
Mycobacterium tuberculosis. Antimicrob. Agents Chemother. 42:20662069.
3. Miyazaki, E., M. Miyazaki, J. M. Chen, R. E. Chaisson, and W. R. Bishai.
1999. Moxifloxacin (BAY128039), a new 8-methoxyquinolone, is active in a
mouse model of tuberculosis. Antimicrob. Agents Chemother. 43:8589.
4. Pletz, M. W., A. De Roux, A. Roth, K. H. Neumann, H. Mauch, and H. Lode.
2004. Early bactericidal activity of moxifloxacin in treatment of pulmonary
tuberculosis: a prospective, randomized study. Antimicrob. Agents Chemother. 48:780782.

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Mathias W. R. Pletz*
Department of International Health
Rollins School of Public Health
Emory University
Atlanta, Georgia
Hartmut Lode
Department of Chest and Infectious Diseases
Chest Hospital Heckeshorn
Berlin, Germany
*Phone: (404) 727-3984
Fax: (404) 712-8419
E-mail: mpletz@sph.emory.edu

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